The gold standard for cancer treatment is surgery. In cases where surgery alone is not curative, multimodality regimens including chemotherapy and radiation treatment are used. About half of all cancer patients today are treated with radiotherapy, either alone or in combination with other treatments. Radiation delivered as external beams offers a relatively simple and practical approach to causing radiation damage to the tumor. Although the intensity, location and timing for external radiation can be well controlled and modulated, disadvantages associated with this technique include the destruction of normal tissue in the path of the beam as well as damage to tissues surrounding the tumor. The risk of damaging surrounding healthy tissue speaks against external radiotherapy to deeply situated tumors and tumors situated next to vital organs. Furthermore, high radiation doses are frequently required to penetrate the tissue. Moreover, in order to be efficient, external radiotherapy often requires the patients to submit themselves to daily hospital visits over extended periods of time.
Systemic radiotherapy, which internally delivers radioactive substances to the tumor, offers solutions to many of the above mentioned disadvantages connected with external radiotherapy.
The most commonly used radionuclides for systemic radiotherapy in clinics today are beta-emitting particles. Beta-emitters with energies between 0.1-2.2 MeV are ideal for the treatment of small to large clusters of tumor cells (Milenic et al., Nature Reviews Drug Discovery, 2004, 3). The maximum tissue penetration range (1-10 mm) and cross-fire effects, i.e. the ability to kill cells indirectly along a longer path length, of beta-particles of such energies thus allows for the targeting of tumor cells in close proximity to neovasculature. Radionuclides such as 131I are used alone, as in the treatment of thyroid cancers, or conjugated with monoclonal antibodies or peptides to allow for tumor-targeting radioimmunotherapy. Ibritumomab tiuexan with 90Y (Zevalin®) and tositumomab coupled with 131I (Bexxar®) are two examples of approved radioimmunotherapy regimens both targeting B lymphocytes to treat B-cell non-Hodgkin lymphoma (Sharkey and Goldenberg, Immunotherapy, 2011, 3:3).
Clinical use of alpha-emitters is less common, but some show clinical potential. As an example, the alpha-emitter 223Ra (Xofigo®) has recently been FDA-approved for treatment of metastatic bone cancer (Shirley and McCormack, Drugs, 2014).
Recent advances in nanotechnology have led to the development of novel nanocarriers designed for cancer detection and screening, in vivo molecular and cellular imaging as well as the delivery of therapeutics. However, despite a large number of publications covering nanosized carriers for cancer therapeutics, relatively few have reached clinical trials, and only a handful are approved by the FDA (Taurin et al., J. Controlled release 2012, 164). Among nanostructures used as drug vehicles, liposomes are most established. Doxil® and DaunoXome®, two liposomal formulations of doxorubicin and daunorubicin respectively, were approved in 1995 and 1996 respectively. Compared to liposomes, polymeric drug carriers should be advantageous as drug carriers due to higher stability, sharper size distribution and more controllable physicochemical and drug release properties. In the list of polymeric materials approved by the FDA for cancer therapeutics, only pegylated proteins e.g. Oncaspar® and Zinostatin Stimalmer® (SMANCS), and Abraxane®, which is paclitaxel bound to albumin, are mentioned (Venditto and Szoka Jr., Adv Drug Rev. 2013, 65:1).
Loading nanocarriers designed for systemic radiotherapy with radionuclides suitable for medical imaging in addition to radionuclides suited for radiotherapy, or a radionuclide suited for both, brings forward a possibility for a theranostic application of nanocarriers in cancer care. Gamma emitters with energies ranging from approximately 75 to 360 keV are suited for gamma detectors and single photon emission computed tomography (SPECT), whereas high-energy positron-emitting radionuclides which yield gamma photons of 511 keV can be applied for positron emission tomography (PET) (Coleman, Cancer. 1991, 67:4). Efforts to create theranostic nanocarriers are reviewed in Luk et al., Theranostics, 2012, 2:12.
The present invention relates to globular, bioinert, chelating polymeric nanostructures with applications in radioisotope therapy and cancer diagnostics. The following literature examples are examples of relevant background publications, which in no way are to be construed as being within the scope of the current invention.
International publication WO 2009/124388 discloses a hydrogel system having a covalently crosslinked polymer matrix core, with some features in common with the central part of the current invention. However, it describes microbeads much larger than the nanostructures of the current invention, it thus falls outside our scope.
United States Patent Application 20140004048 describes a nanostructure which in conformity with the nanostructure presented in the current disclosure in some embodiments has a central and a peripheral part, but where the peripheral part comprises well defined dendritic structures rather than the random polymers which are advantageous for the present invention.
Materials with a core-shell structure designed for carrying e.g. chemotherapeutic agents, are generally not suited for the application of the current invention e.g. U.S. Pat. No. 8,592,036 which describe nano-constructs where the central part is biodegradable and hence outside the scope of the current invention.
European Patent Application EP1500670 describes a material which in certain embodiments has features in common with the current invention but where the degree of crosslinking is low and is hence outside the scope of the current invention.
Structures in WO 2003/089106A2 fall outside the scope of the current invention, as it covers materials where the central part of the structures, in some embodiments is branched. They also have a peripheral part, but the structures lack the feature of carrying chelating groups which is central for the current invention.
Moreover, several approaches described in the literature (e.g. Ocal H., et al., Drug Development and Industrial Pharmacy, 2014, 40:4; WO/2009115579; WO 2011/078803), involve biodegradable materials which allow for fast or slow release of the carried therapeutic agent. The structure presented in the current invention is bioinert, as biodegradability would cause undesirable and uncontrolled loss of the radioactive isotope from the nanostructure and hence cause radiation damage in important organs.
A number of nanoparticle-based radiation delivery agents are known in the art (e.g. Ting G. et al., Journal of Biomedicine and Biotechnology, 2010; Luk et al., Theranostics. 2012, 2:12). Several approaches involve actively targeted materials, in which the nanostructure is linked to a bioconjugate, e.g. an antibody or a peptide which allows for tumor-targeting delivery through molecular interaction. Actively targeted approaches are often limited by insufficient delivery of therapeutic agents to tumor sites due to relatively low and heterogeneous expression of tumor specific targets. Moreover, expression of target proteins on non-tumorigenic cells could lead to systemic toxicity. Sometimes the introduction of the bioconjugate leads to increased liver uptake.
Many of the approaches to radiotherapy involving nanocarriers suggested in the literature, e.g. nanocarriers based on liposomes (Malam et al., Trends Pharmacol Sci. 2009, 30:11) suffer from the drawback that the radioactive isotope has to be incorporated in or encapsulated by or covalently bound to the nanocarrier by one or more chemical steps. This is usually not desirable since normally the radioisotope would be supplied by a third party and incorporated in the nanocarrier at a hospital with limited laboratory facilities. The materials of the current invention overcome this by being able to rapidly bind the isotopes when supplied in a multivalent cationic form, more specifically each radioisotope ion having a charge of plus two, three, or four. United States Patent Application 20040258614 discloses a material in which the radioisotope is covalently bound to the carrier. In the current invention the radioisotope is selected so that it can be bound by electrostatic interactions with the nanocarrier as opposed to being covalently bound which has the advantage of making the preparation of the therapeutic agent simpler and more user-friendly. Thus, the material in the above-mentioned patent application is outside the scope of the present invention.
Also, many of the approaches to radioisotope therapy involving alleged nanocarriers mentioned in the literature suffer from the drawback that the nanocarrier is not really a nanocarrier as it is larger than 100 nm and due to its large size suffers from the drawback of not delivering the radioisotope to the tumor tissue in an effective way. The materials disclosed in the current invention focus on nanocarriers or nanomaterials that are above the threshold where they would be excreted through the kidneys and hence either cause damage and/or be lost from the body while at the same time being small enough (below 100 nm diameter) to be able to leak out through defective capillaries and diffuse through the intracellular matrix and deliver the radioactivity to the tumor cells. WO 2004/040972 is one example of a carrier that is larger than 100 nm, and thus lies outside the scope of the current invention. Furthermore, the rationale for nanosized materials being suitable as tumor-targeting radiation carriers is related to the enhanced permeation and retention (EPR) effect. The EPR effect is based on the fact that whereas the capillaries of healthy tissues are virtually impermeable to molecules larger than 3-4 nm, capillaries of fast-growing tumor tissue are much leakier. In addition, solid tumors tend to lack functional lymphatics. Combined, these features limit the removal of extravasated nanomaterials from most solid tumors. Because EPR-mediated drug targeting exclusively relies on the pathological properties of the target tissue, that is, enhanced leakiness and poor lymphatic drainage, it is generally referred to as passive tumor targeting.
Although in no way certain or limiting, it is conceivable that the EPR effect is the basis of the favorable tumor delivery properties of the materials of the current invention.